Coronavirus disease 2019 and pityriasis rosea: A review of the immunological connection

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is characterized by the activation of a cytokine storm derived from an excess release of cytokine (interleukin [IL]‐6, interferon [IFN] I, C‐X‐C motif chemokine ligand [CXCL]10, tumor necrosis factor [TNF]‐α, macrophage inflammatory protein [MIP]1) due to an uncontrolled immune activation. There has been a fivefold increase in the number of cases of pityriasis rosea during the SARS‐CoV‐2 pandemic. Using the keywords “pityriasis” and “COVID‐19”, we carried out a PubMed search, including all articles in the English language published until November 2021. We aimed to investigate the possible connection between SARS‐CoV‐2 and pityriasis rosea (PR). Pityriasis could be considered an immunological disease due to the involvement of cytokines and chemokines. Our analysis yielded 65 articles of which 53 were not considered; the others (n = 12) concerning the association between PR and COVID‐19 were included in our study. We suggest two mechanisms underlying the involvement of the skin in viral infections: (i) viruses directly affecting the skin and/or inducing host immune response thus causing cutaneous manifestations; and (ii) viruses as a possible inducer of the reactivation of another virus. The first mechanism is probably related to a release of pro‐inflammatory cytokine and infection‐related biomarkers; in the second, several pathways could be involved in the reactivation of other latent viruses (human herpesviruses 6 and 7), such as a cytokine–cytokine receptor interaction, the Janus kinase–signal transducer and activator of transcription signaling pathway, and the IL‐17 signaling pathway. We thus believe that a cytokine storm could be directly or indirectly responsible for a cutaneous manifestation. More investigations are needed to find specific pathways involved and thus confirm our speculations.


| INTRODUC TI ON
for tissue injury and more severe Sars-CoV-2 damage. 2 Khesht et al. speculate that the increase of TNFα and IL-6 might reduce the suppressive function of Treg by inhibiting the transforming growth factor (TGF)β and forkhead box P3 (FOXP3). 3 In mild cases, an anti-inflammatory response mediated by  and IL-10 is prevalent, which suppresses Th1 cell differentiation and proliferation and inhibits pro-inflammatory cytokine production. 2 Increasing evidence suggests that type I IFN pathways are key to the immune-mediated clearance of SARS-CoV-2. Severe COVID-19 infections have been correlated with low blood levels of type I IFN and low white blood cell expression of type I IFN-inducible genes. In this way, deficiencies in the type I IFN pathway, due to inherited mutations or the development of autoantibodies, predispose patients to develop severe COVID-19 4 Below, Figure 1 summarizes the main immunological mechanisms through which SARS-CoV-2 causes clinical manifestations.

| CutaneousmanifestationsofSARS-CoV-2
Since the start of the COVID-19 pandemic, multiple studies have reported that SARS-CoV-2 can be associated with dermatological manifestations. The association between different types of cutaneous involvement and the severity of COVID-19 is likely due to the varying immune response following SARS-CoV-2 infection. Indeed, livedo racemosa and retiform purpura are associated with a more severe disease course and higher mortality. In contrast, viral exanthem and inflammatory lesions, such as urticarial and vesicular eruptions, seem to be associated with a less severe COVID-19 disease course which were reported more frequently for inpatients. 5 In some cases, F I G U R E 1 The immunological mechanisms activated by SARS-CoV2 infection are closely related to the cytokine storm and they can be divided into three branches: Th1-mediated response, Th17-mediated response, and anti-inflammatory response which is generally activated in cases of mild disease and could inhibit the Th1 response. CXCL10, C-X-C motif chemokine ligand; GM-CSF, granulocyte-macrophage Colony-Stimulating Factor; IFN-gamma, Interferon-gamma; IL-1,4,6,10,21,22, Interleukin-1,2,4,6,10,21,22; MCP-1, monocyte chemoattractant protein 1; MIP-1A, macrophage inflammatory protein-1 alpha; SOCS-3, Suppressor of cytokine signaling 3; TNF, tumor necrosis factor. cutaneous involvement may represent a visual marker for the early identification of infection. COVID-19 cutaneous clinical patterns include morbilliform, vesiculopapular, pernio-like lesions and purpura. 6 SARS-CoV-2 is related to the onset of several viroses, such as those mediated by herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV), which can appear with a plethora of skin manifestations, through a possible viral reactivation mechanism. 7 COVID-19 can be also associated with various dermatological diseases. Among these, a relative increase in pityriasis rosea (PR) and PR-like rash was reported during the pandemic, despite restrictions imposed by social distancing and despite the recommendation to limit non-urgent outpatient services during the pandemic. 8,9 Using clinical and histopathological findings, Öncü et al. managed to establish the diagnosis of PR after COVID-19 infection. Histopathology of the biopsy of one lesion showed focal parakeratotic peaks, spongiosis, focal spongiotic vesiculation, lymphocyte exocytosis, mildly irregular acanthosis with mild homogenization of collagen in the dermis, mild to moderate perivascular erythrocyte infiltration in the superficial vascular plexus, scattered lymphocyte infiltration, and sparse lymphocytes. 10

| PR:Pathogenesisandimmunologicalaspects
Pityriasis rosea is an acute, self-limiting exanthematous disease, predominantly affecting children and young adults. Some epidemiological features (seasonal variation and clustering in households) suggest that PR may be infectious. Reactivation of latent human herpesviruses (HHV)-6 and -7 infections has been suggested as the most probable etiological agent.
Pityriasis rosea typically begins with a single, erythematous scaly plaque (herald patch or mother spot) followed by a secondary eruption consisting of smaller scaly papulosquamous lesions on the cleavage lines of the trunk in a Christmas tree-like shape. It appears in crops at intervals of a few days and reaches its acme in approximately 2 weeks. The duration may vary from 2 weeks to a few months, and constitutional symptoms may precede or accompany the skin eruption (general malaise, sore throat, mild fever, fatigue, nausea, headache, joint pain, swelling of lymph nodes). 11,12 The etiopathogenetic mechanisms underlying PR are still not and activates gene expression. These genes exert pro-inflammatory effects by increasing antigen processing and presentation, and anti-inflammatory effects due to their apoptotic and antiproliferative functions. CXCL10 or interferonγ-induced protein 10 (IP-10) is an IFN-inducible chemokine, produced by neutrophils and keratinocytes, which recruits natural killer cells, CD4 and CD8 T lymphocytes. 15 In Figure 2, the hive represents the effect that each mediator determines at the level of skin cellularity in patients with PR.The purpose of this review is to analyze the connection between SARS-CoV-2 and PR. Our aim is to investigate whether COVID-19 can cause cutaneous manifestation compatible with PR, through an immune dysregulation or if it is caused by the reactivation of HHV-6/ HHV-7 followed by COVID-19 infection.

| ME THODS
We carried out a PubMed search including all articles in English published until November 2021. We used the keywords "pityriasis" and "COVID-19", without time limits.

| RE SULTSANDD ISCUSS I ON
Our analysis yielded 65 articles of which 53 were not considered because the title and/or abstract suggested that they did not cover the topic of interest (n = 28), were not written in English (n = 3), or were not relevant to the association between PR and COVID-19 (n = 22).
The others, which reported on a possible association between PR and COVID-19 (n = 12), were included.  These results suggest that these inflammatory mediators may synergistically modulate PR pathogenesis (Figures 4 and 5).
Another mechanism involved in viral reactivation could be In fact, in preclinical trials of the Moderna vaccine, the incidence of PR was 0.9%. 45 However, several researches have reported cases of PR after COVID-19 vaccines with an incidence higher than that reported by the EMA in pre-clinical studies. 17,46 It must be considered that the vaccination campaign is still ongoing worldwide, so these data are reliable, but not definitive. This suggests that anti-SARS-CoV-2 vaccines can also cause immune dysregulations resulting in a commitment of the immune system and a deviation of its cell-mediated control over other latent viruses. 47 The reactivation of herpes viruses after vaccine administration could be responsible for the same extrapulmonary manifestations of the infection, but to a lesser extent.

| CLOS INGREMARK S
In conclusion, in the literature, many cutaneous manifestations have been described in patients affected by SARS-CoV-2. Our analysis of the mechanisms underlying the onset of PR cutaneous manifestations, suggests two causes.
Firstly, the cytokine storm, which characterizes SARS-CoV-2 infection, could be responsible for a direct effect on the skin, resulting in cutaneous inflammation. 48 In fact, during the COVID-19 pandemic there has been an increased incidence of other cutaneous diseases,

F I G U R E 5
The main immunological mechanisms probably involved in the pathogenesis of PR following SARS-CoV-2 infection are described: a direct pathway ending with the production of pro-inflammatory cytokines and an indirect pathway involving IFN-inducible genes. The yellow helical structure represents viral RNA. The green structure is a mitochondrion. CXCR3, C-X-C motif chemokine receptor 3; CXCL10, C-X-C motif chemokine ligand; HHV, human herpesviruses; IL, interleukin; IFN, interferon; IRF, IFN-regulatory factor; JAK, Janus kinase; MAVS, mitochondrial antiviral-signaling protein; MCP-1, monocyte chemoattractant protein 1; NF-κB R.E., nuclear factor-κB responsive element; NK, natural killer; "P", phosphorylation; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor.
such as urticaria, psoriasis, alopecia, and chilblain-like skin lesions. 16 Gallman et al. believe that dysregulation of the humoral immune response is a feature of SARS-CoV-2 infection and may contribute to skin manifestations of COVID-19-associated disease, also through autoimmunity mechanisms, such as molecular mimicry or bystander activation. 4 These cutaneous manifestations could be an indicator of latent COVID-19 infections because these skin lesions can precede the onset of respiratory SARS-CoV-2 symptoms. For these reasons, IHC analysis of skin biopsies may represent a useful tool in selected patients with a suspected COVID-19 diagnosis. 22 The second mechanism that may be involved in the increased inci- This is particularly relevant to dermatology as visual cues are the keystone in identifying most dermatological pathologies. 50 The efficacy of this new system always depends on the quality of the video, images sent, and patient compliance. Nevertheless, legislation and guidelines for putting teledermatology in practice whilst protecting patient privacy and data security are needed.
We hope that the evidence given in this review will be useful in the identification, management, and treatment of future pandemic viral infections in a scenario based on precision medicine.

ACK N OWLED G M ENTS
Open Access Funding provided by Universita degli Studi di Messina within the CRUI-CARE Agreement.

CO N FLI C TO FI NTE R E S T
None declared.